Angiotensin II receptor blocking 2,3,6 substituted quinazolinones

ABSTRACT

The invention provides novel 2,3,6-substituted quinazolinones having the formula   &lt;IMAGE&gt; Formula I  wherein X, R, R6 are described in the specification which have activity as angiotensin II (AII) antagonists.

BACKGROUND OF THE INVENTION

1. Field of the Invention This invention relates to certain novel 2,3,6substituted quinazolinone compounds which have demonstrated activity asangiotensin II (AII) antagonists and are therefore useful in alleviatingangiotensin induced hypertension and for treating congestive heartfailure.

SUMMARY OF THE INVENTION

According to the present invention, there are provided novel compoundsof Formula I which have angiotensin II-antagonizing properties and areuseful as antihypertensives: ##STR2## wherein: R is ##STR3## X isstraight or branched alkyl of 3 to 5 carbon atoms; R⁶ is ##STR4## R²⁰ isH, straight chain lower alkyl of 1 to 4 carbon atoms, phenyl,substituted phenyl (substitution selected from mono-lower alkyl of 1 to3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms),benzyl, substituted benzyl (substitution selected from mono-lower alkylof 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbonatoms);

R²¹ is H, straight chain lower alkyl of 1 to 4 carbon atoms, phenyl,substituted phenyl (substitution selected from mono-lower alkyl of 1 to3 carbon atoms, trifluoromethyl, nitro, 0-alkyl of 1 to 3 carbon atoms),benzyl, substituted benzyl (substitution selected from mono-lower alkylof 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbonatoms);

R²² is H, straight chain lower alkyl of 1 to 4 carbon atoms, phenyl,substituted phenyl (substitution selected from mono-lower alkyl of 1 to3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms),benzyl, substituted benzyl (substitution selected from mono-lower alkylof 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbonatoms);

R²³ is H, straight chain lower alkyl of 1 to 4 carbon atoms, phenyl,substituted phenyl (substitution selected from mono-lower alkyl of 1 to3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms),benzyl, substituted benzyl (substitution selected from mono-lower alkylof 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbonatoms);

n is 1 or 2;

and pharmaceutically acceptable salts of these compounds.

The present invention also provides novel intermediate compounds,methods for making the novel 2,3,6-substituted quinazolinoneangiotension II antagonizing compounds, methods for making the novelintermediates, methods of using the novel quinazolinone angiotensin IIantagonizing compounds to treat hypertension, congestive heart failureand to antagonize the effects of angiotensin II.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of the present invention are prepared according tothe following reaction schemes.

Referring to Scheme I, the corresponding anthranilic acid 2 where R¹⁰ isI, is heated to reflux in alkyl acid anhydride 3 wherein X is alkyl of 3to 5 carbon atoms to provide the 4H-3,1-benzoxain-4-ones 4 which areisolated by concentrating the reaction mixtures and used without furtherpurification. When the 4H-3,1-benzoxazin-4-ones 4 are refluxed in ethylalcohol containing ammonia, or ammonium hydroxide solution, thequinazolinone intermediates 5 are obtained. ##STR5##

As outlined in Scheme II, quinazolinone intermediates 5 are reacted withcopper(I) cyanide to give quinazolinone 6. Reaction of 6 with sodiumazide in the presence of tri-n-butyltin chloride in refluxing xyleneaffords the desired tetrazole 7. Contemplated equivalents oftri-n-butyltin chloride include tri-(lower alkyl C₁ -C₄) tin chloridesand bromides. Contemplated equivalents to sodium azide include potassiumazide, cesium azide, calcium azide and lithium azide.

As illustrated in Scheme III, 7 is reacted with bromosubstituted olefin8 where R²⁰, R²¹, R²², R²³ and n are hereinbefore defined to givesubstituted product 9. The reaction of substituted quinazolinone 9 withbiphenyl 10 where R¹⁸ is cyano prepared by the methods outlined in D.Carini, J. Med. Chem. 34, 2525-2547(1991) gives coupled product 11 bydissolving 9 and 10 in acetone or another suitable solvent such asN,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone,methanol, ethanol, t-butanol, tetrahydrofuran, dioxane ordimethylsulfoxide, in the presence of excess potassium carbonate oranother suitable base such as sodium carbonate, cesium carbonate, sodiumhydride, potassium hydride, sodium methoxide, sodium ethoxide, lithiummethoxide, sodium t-butoxide, potassium t-butoxide, lithiumdiisopropylamide (LDA) or lithium hexamethyldisilazide for 2-48 hours,at 20°-60° C. The coupled product 11 may be purified by chromatographyor used as in further transormations. Heating 11 in diphenylether givescyclized product 12. ##STR6## Reaction of 12 where R¹⁸ is cyano withsodium azide in the presence of tri-n-butyltin chloride in refluxingxylene affords the desired tetrazole 13. Contemplated equivalents oftri-n-butyltin chloride include tri-(lower alkyl C₁ -C₄) tin chloridesand bromides. Contemplated equivalents to sodium azide include potassiumazide, cesium azide, calcium azide and lithium azide.

Reactions are performed in a solvent appropriate to the reagents andmaterials employed and suitable for the transformation being effected.It is understood by those skilled in the art of organic synthesis thatthe various functionalities present on the molecule must be consistentwith the chemical transformations proposed. This may necessitatejudgement as to the order of synthetic steps, protecting groups, ifrequired, and deprotection conditions. Substituents on the startingmaterials may be incompatible with some of the reaction conditions. Suchrestrictions to the substituents which are compatible with the reactionconditions will be apparent to one skilled in the art.

Pharmaceutically suitable salts include both the metallic (inorganic)salts and organic salts; a list of which is given in Remington'sPharmaceutical Sciences, 17th Edition, pg. 1418 (1985). It is well knownto one skilled in the art that an appropriate salt form is chosen basedon physical and chemical stability, flowability, hydroscopicity andsolubility. Preferred salts of this invention for the reasons citedabove include potassium, sodium, calcium, magnesium and ammonium salts.

Some of the compounds of the hereinbefore described schemes have centersof asymmetry. The compounds may, therefore, exist in at least two andoften more stereoisomeric forms. The present invention encompasses allstereoisomers of the compounds whether free from other stereoisomers oradmixed with other stereoisomers in any proportion and thus includes,for instance, racemic mixture of enantiomers as well as thediastereomeric mixture of isomers. The absolute configuration of anycompound may be determined by conventional X-ray crystallography.

While the invention has been illustrated using the trityl protectinggroup on the tetrazole, it will be apparent to those skilled in the artthat other nitrogen protecting groups may be utilized. Contemplatedequivalent protecting groups include, benzyl, p-nitrobenzyl,propionitrile or any other protecting group suitable for protecting thetetrazole nitrogen. Additionally, it will be apparent to those skilledin the art that removal of the various nitrogen protecting groups, otherthan trityl, may require methods other than dilute acid.

The compounds of this invention and their preparation are illustrated bythe following non-limiting examples.

EXAMPLE 1 2-Butyl-6-iodo-4(1H)-quinazolinone

To 20.0 g of 2-amino-5-iodobenzoic acid is added 75 ml of valericanhydride. The mixture is heated at reflux for 18 hours and thenconcentrated under reduced pressure. The resulting residue is suspendedin 200 ml of 30% ammonium hydroxide and 300 ml of ethyl alcohol. Thismixture is heated at reflux for 18 hours and then allowed to cool toroom temperature. After cooling, the precipitate is collected andcrystallized from ethyl alcohol to give 3.22 g of the desired product asa solid,

m.p. 258°-260° C.

EXAMPLE 2 2-Butyl-6-cyano-4(1-H)-quinazolinone

A mixture of 6.4 g of 2-butyl-6-iodo-4(1H)-quinazolinone in 25 ml ofpyridine is added 3.6 g of copper(I) cyanide followed by heating atreflux for 16 hours. The reaction mixture is poured into water andstirred at room temperature for 8 hours. The suspension is filtered andthe cake washed well with water and air dried. The solid is dissolved in3:1 chloroform-methanol and dried with MgSO₄. The volatiles areevaporated in vacuo to give 3.2 g of the desired pro-duct as a solid.m.p. 243°-45° C.

EXAMPLE 3 2-Butyl-6-(1H-tetrazol-5-yl)-4(1H)-quinazolinone

A mixture of 1.1 g of 2-Butyl-6-cyano-4(1H)-quinazolinone 3.2 g oftri-n-butyltin chloride and 640 mg of sodium azide in 30 ml of tolueneis heated at reflux for 48 hours. The reaction mixture is cooled to roomtemperature and dry HCl gas passed through the reaction mixture for 10minutes. The reaction mixture is diluted with hexane and filtered. Theresidue is dried, washed with water and dried to give 1.5 g of thedesired product as a solid, m.p. 225° C.

EXAMPLE 42-Butyl-6-[2-(4-pentenyl)-2H-tetrazol-5-yl]-4(1H)-quinazolinone

A mixture of 3.0 g of 2-butyl-6-(1H-tetrazol-5-yl)-4(1H)-quinazolinone,2.2 g of 5-bromo-1-pentene and 2 ml of N,N-diisopropylethylamine in 50ml of tetrahydrofuran is refluxed for 24 hours. The volatiles areevaporated in vacuo to a residue which is partitioned between chloroformand water. The organic layer is dried over MgSO₄, filtered andevaporated in vacuo to a residue which is purified by columnchromatography on silica gel by elution with 3:2 ethyl acetate-hexanesto give a residue which crystallizes from ethyl acetate-hexanes to give2.0 g of the desired product as a solid, m.p. 130° C.

EXAMPLE 5 2-Butyl-6-[2-(5-hexenyl-2H-tetrazin-5-yl]-4(1H)-quinazolinone

A mixture of 2.7 g of 2-butyl-6-(1H-tetrazol-5-yl)-4(1H)-quinazolinone,3 ml of 5-bromo-1-hexene, 3 ml of diisopropylamine in 50 ml oftetrahydrofuran is refluxed for 24 hours. The volatiles are evaporatedin vacuo to a residue which is partitioned between chloroform and water.The organic layer is dried over MgSO₄, filtered and evaporated in vacuoto a residue which is purified by column chromatography on silica gel byeluting with 3:2 ethyl acetate-hexanes to give 2.9 g of the desiredproduct as a solid, m.p. 140° C.

EXAMPLE 64'-[[2-Butyl-4-oxo-6-[2-(4-pentenyl)-2H-tetrazol-5-yl]-3(4H)-quinazolinyl]methyl]-[1,1'-biphenyl]2-carbonitrile

A mixture of 1.01 g of2-butyl-6-[2-(4-pentenyl)-2H-tetrazol-5-yl]-4(1H)-quinazolinone, 1.09 gof 4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile and 2.0 g of potassiumcarbonate in 100 ml of acetone is refluxed for 24 hours. The reactionmixture is filtered and the filtrate evaporated in vacuo to a residuewhich is purified by chromatography on silica gel by elution with 30%ethyl acetate-hexanes to give 1.5 g of the desired product as a yellowfoam.

M⁺ =529.6, M⁺¹ =530.

EXAMPLE 74'-[[2-Butyl-6-[1-(5-hexenyl)-1H-tetrazol-5-yl]-4-oxo-3(4H)-quinazolinyl]methyl][1,1'-biphenyl]-2-carbonitrile

A mixture of 1.7 g of2-butyl-6-[2-(4-hexenyl)-2H-tetrazol-5-yl]-4(1H)-quinazolinone, 1.9 g of4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile and 3.0 g of potassiumcarbonate in 100 ml of acetone is refluxed for 24 hours. The reactionmixture is filtered and the filtrate evaporated to a residue which ispurified by chromatography on silica gel by elution with 30% ethylacetate-hexanes to give 2.3 g of the desired product as a yellow foam.

M⁺ =544.

EXAMPLE 8 4'-[2-Butyl-4-oxo-6-(3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3(4H)-quinazolinyl][1,1-biphenyl]-2-carbonitrile

A mixture of 1.01 g of4'-[[2-Butyl-4-oxo-6-[2-(4-pentenyl)-2H-tetrazol-5-yl]-3(4H)-quinazolinyl]-methyl]-[1,1'-biphenyl]-2-carbonitrileis suspended in 100 ml of diphenylether and heated for 3 hours. Thereaction mixture is cooled to room temperature and diluted with 1L ofhexanes. The oily compound is separated from the hexanes-diphenyl ethermixture and purified by column chromatography on silica gel by elutionwith 75% ethyl acetate-hexanes to give 2.1 g of the desired product as ayellow solid.

M⁺ =501.

EXAMPLE 94'-[[2-Butyl-6-(3,3a,4,5,6,7-hexahydro-pyrazolo-[1,5-a]pyridin-2-yl)-4-oxo-3(4H)-quinazolinyl]-methyl][1,1'-biphenyl]-2-carbonitrile

A mixture of 5.43 g of4'-[[2-butyl-6-[1-(5-hexenyl)-1H-tetrazol-5-yl]-4-oxo-3(4H)-quinazolinyl]methyl][1,1'-biphenyl]-2-carbonitrilein 100 ml of diphenylether is heated for 3 hours. The reaction mixtureis cooled to room temperature and diluted with 1L of hexanes. The oilycompound is separated from the hexanes-diphenylether mixture andpurified by column chromatography on silica gel by eution with 75% ethylacetate-hexanes to give 2.1 g of the desired product as solid.

M⁺ 515.

EXAMPLE 102-Butyl-6-(3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]-pyrazol-2-yl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

A mixture of 1.0 g of4'-[2-butyl-4-oxo-6-(3a,4,5,6-tetrahydro-3H-pyrrolo-[1,2-b]pyrazol-2-yl)-3(4H)-quinazolinyl][1,1-biphenyl]-2-carbonitrile,3.25 g of tri-n-butyl tin chloride and 600 mg of sodium azide in 500 mlof xylene is refluxed for 48 hours. The reaction mixture is cooled toroom temperature and 5 ml of methanol added. Gaseous HCl is passedthrough the reaction mixture for 10 minutes and the resulting solidcollected by filtration, washed with hexanes and water. The solid ispurified by column chromatography on silica gel by elution with 90%ethyl acetate-10% hexanes containing 2 ml of methanol to give 600 mg ofthe desired product as yellow crystals, m.p. 126° C.

M⁺ H=545.

EXAMPLE 112-Butyl-6-(3,3a,4,5,6,7-hexahydropyrazolo[1,5-a]-pyridin-2-yl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl-4(3H)-quinazolinone

A mixture of 2.0 g of4'-[[2-Butyl-6-(3,3a,4,5,6,7-hexahydro-pyrazolo-[1,5-a]pyridin-2-yl)-4-oxo-3(4H)-quinazolinyl]methyl][1,1'-biphenyl]-2-carbonitrile,6.5 g of tributyltin chloride and 1.2 g of sodium azide in 500 ml ofxylene is refluxed for 48 hours. The reaction mixture is cooled to roomtemperature and 5 ml of methanol added followed by the addition ofgaseous HCl for 10 minutes. The separated solid is filtered, washed withhexane and water then purified by column chromatography on silica gel byelution with 90% ethyl acetate-10% hexanes containing 2 ml of methanolto give 800 mg of the desired product as yellow crystals, m.p. 86°-87°C.

ANGIOTENSIN II ANTAGONISTS IN VITRO TESTS Materials and Methods

Beef adrenals are obtained from a local slaughter house (Maxwell-Cohen).[¹²⁵ I](Sar¹,ILe⁸)-AngII, S.A. 2200 Ci/mmole, is purchased from Dupont(NEN®, Boston, Mass.). All unlabeled AngII analogs, Dimethylsulfoxide(DMSO), nucleotides, bovine serum albumin (BSA) are purchased from SigmaChemical Co., St. Louis, MO U.S.A.

Preparation of Membranes

Approximately sixteen (16) to twenty (20) beef adrenal glands areprocessed as follows: fresh adrenal glands received on crushed ice arecleaned of fatty tissues and the tough membranes encapsulating theglands are removed and discarded. The brownish tissue forming theadrenal cortex is scraped off and finely minced with scissors beforehomogenization. Care is taken to avoid contamination with medullarytissue during dissection. The scraped cortices are suspended in twentyvolumes of an ice-cold buffer medium consisting of 10 mM Tris.HCl (pH7.4 at 22° C.) and containing 1.0 mM EDTA and 0.2M sucrose. Unlessotherwise indicated, all subsequent operations are done at 4° C. Thetissue is homogenized in a glass homogenizer with a motor-driven teflonpestle with a clearance of 1.0 mm. The homogenate is centrifuged firstat low speed (3,000 ×g) for 10 min. The resulting pellet is discardedand the supernatant fluid recentrifuged at 10,000×g for 15 minutes togive a P₂ pellet. This P₂ pellet is discarded and the liquid phase iscarefully decanted off in clean centrifuge tubes and recentrifuged athigh speed (100,000×g) for 60 min. The translucent final pellet isharvested and combined in a small volume (20-20.0 ml) of 50.0 mMTris.HCl buffer, pH 7.2. A 100 ul aliquot is withdrawn and the proteincontent of the preparation is determined by the Lowry's method (Lowry,O.H., Rosebrough, N.F., Farr, A.L. and Randall, R.J., Proteinmeasurement with Folin phenol reagent. J. Biol. Chem., 48, 265-275,1951). The pelleted membrane is reconstituted in 50.0 mM Tris.HCl buffercontaining 0.1 mM of phenylmethylsulfonyl fluoride (PMSF) to giveapproximately a protein concentration of 2.5 mg per ml of tissuesuspension. The membrane preparation is finally aliquoted in 1.0 mlvolumes and stored at -70° C. until use in the binding assays.

Receptor Binding Assay Binding of[¹²⁵ I](Sar¹,Ile⁸)AngII

The binding of [¹²⁵ I](Sar¹,Ile⁸)ANGII to microsomal membranes isinitiated by the addition of reconstituted membranes (1:10 vols.) infreshly made 50.0 mM Tris.HCl buffer, pH 7.4 containing 0.25% heatinactivated bovine serum albumin (BSA): 80 ul membrane protein (10 to 20ug/assay) to wells already containing 100 ul of incubation buffer (asdescribed above) and 20 ul [¹²⁵ I](Sar¹,Ile⁸)AngII (Specific Activity,2200 Ci/mmole). Non-specific binding is measured in the presence of 1.0uM unlabeled (Sar¹,Ile⁸)AngII, added in 20 ul volume. Specific bindingfor [¹²⁵ I](Sar¹,Ile⁸) AngII is greater than 90%. In competitionstudies, experimental compounds are diluted in dimethylsulfoxide (DMSO)and added in 20 ul to wells before the introduction of tissue membranes.This concentration of DMSO is found to have no negative effects on thebinding of [¹²⁵ I](Sar¹,Ile⁸) AngII to the membranes. Assays areperformed in triplicate. The wells are left undisturbed for 60 min. atroom temperature. Following incubation, all wells are harvested at oncewith a Brandel® Harvester especially designed for a 96 well plate(Brandel® Biomedical Research & Development Labs. Inc., Gaithersburg,Md., U.S.A.). The filter discs are washed with 10×1.0 ml of cold 0.9%NaCl to remove unbound ligand. Presoaking the filter sheet in 0.1%polyethyleneimine in normal saline (PEI/Saline) greatly reduces theradioactivity retained by the filter blanks. This method is routinelyused. The filters are removed from the filter grid and counted in aParkard® Cobra Gamma Counter for 1 min. (Packard Instrument Co., DownersGrove, Ill., U.S.A.). The binding data are analyzed by the non-linearinteractive "LUNDON-1" program (LUNDON SOFTWARE Inc., Cleveland, OhioU.S.A.). Compounds that displace 50% of the labelled angiotensin II atthe screening dose of 50 μM are considered active compounds and are thenevaluated in concentration-response experiments to determine their IC₅₀values. The results are shown in Table I.

                  TABLE I                                                         ______________________________________                                         ##STR7##                                                                                                    Angiotensin II                                 Ex.                            Receptor                                       No.  R.sup.6        X          Binding IC.sub.50 (M)                          ______________________________________                                        10                                                                                  ##STR8##      (CH.sub.2).sub.3 CH.sub.3                                                                1.02 × 10.sup.-7                         11                                                                                  ##STR9##      (CH.sub.2).sub.3 CH.sub.3                                                                5.64 × 10.sup.-8                         ______________________________________                                    

As can be seen from Table I, the compounds demonstrate excellentAngiotensin II Receptor Binding activity.

The enzyme renin acts on a blood plasma α₂ -globulin, angiotensinogen,to produce angiotensin I, which is then converted by angiotensinconverting enzyme to AII. The substance AII is a powerful vasopressoragent which is implicated as a causative agent for producing high bloodpressure in mammals. Therefore, compounds which inhibit the action ofthe hormone angiotensin II (AII) are useful in alleviating angiotensininduced hypertension.

The compounds of this invention inhibit the action of AII. Byadministering a compound of this invention to a rat, and thenchallenging with angiotensin II, a blockage of the vasopressor responseis realized. The results of this test on representative compounds ofthis invention are shown in Table II.

AII CHALLENGE

Conscious Male Okamoto-Aoki SHR, 16-20 weeks old, weighing approximately330 g are purchased from Charles River Labs (Wilmington, Mass.).Conscious rats are restrained in a supine position with elastic tape.The area at the base of the tail is locally anesthetized by subcutaneousinfiltration with 2% procaine. The ventral caudal artery and vein areisolated, and a cannula made of polyethylene (PE) 10-20 tubing (fusedtogether by heat) is passed into the lower abdominal aorta and venacava, respectively. The cannula is secured, heparinized (1,000 I.U./ml),sealed and the wound is closed. The animals are placed in plastiorestraininq cages in an upright position. The cannula is attached to aStatham P23Db pressure transducer, and pulsatile blood pressure isrecorded to 10-15 minutes with a Gould Brush recorder. (Chan et al.,(Drug Development Res., 18:75-94, 1989).

Angiotensin II (human sequence, Sigma Chem. Co., St. Louis, Mo.) of 0.05and 0.1 mcg/kg i.v. is injected into all rats (predosing response). Thena test compound, vehicle or a known angiotensin II antagonist isadministered i.v., i.p. or orally to each set of rats. The two doses ofangiotensin II are given to each rat again at 30, 60, 90, 120, 180, 240and 300 minutes post dosing the compound or vehicle. The vasopressorresponse of angiotensin II is measured for the increase in systolicblood pressure in mmHg. The percentage of antagonism or blockade of thevasopressor response of angiotensin II by a compound is calculated usingthe vasopressor response (increase in systolic blood pressure) ofangiotensin II of each rat predosing the compound as 100%. A compound isconsidered active if at 30 mg/kg i.v. it antagonized at least 50% of theresponse.

    __________________________________________________________________________    % INHIBITION (ANGIOTENSIN BLOCKAGE) OF ANGIOTENSIN II (All)                   VASOPRESSOR RESPONSE                                                                 Dose All Dose                                                                            Min Post                                                                           Control                                                                             Response  Average                                                                            %                                 Ex. No.                                                                              (mg/kg)                                                                            mcg/kg IV                                                                           Dose Before All                                                                          After All                                                                          Change                                                                             Change                                                                             Inhibition                        __________________________________________________________________________    CONTROL     0.05   0   235   280  45   35                                                            250   275  25                                                      0.1        225   285  60   50                                                            235   275  40                                          Ex. No.                                                                              3 IV 0.05   30  230   242  12   13.5 61                                10                     240   255  15                                                      0.1        230   250  20   22.5 55                                                       235   260  25                                                      0.05   60  225   255  30   32.5  7                                                       235   270  35                                                      0.1        230   255  25   22.5 55                                                       240   260  20                                                      0.05   90  225   255  30   20   43                                                       240   250  10                                                      0.1        240   265  25   25   50                                                       235   260  25                                                      0.05  120  225   250  25   20   43                                                       215   230  15                                                      0.1        235   265  30   25   50                                                       220   240  20                                                      0.05  180  210   235  25   22.5 36                                                       215   235  20                                                      0.1        215   245  30   27.5 45                                                       225   250  25                                                      0.05  240  210   230  20   17.5 50                                                       220   235  15                                          __________________________________________________________________________     SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weights(s): 405, 400 grams    

                0.1        225   250  25   25   50                                                       215   240  25                                                      0.05  300  215   250  35   32.5  7                                                       215   245  30                                                      0.1        210   255  45   35   30                                                       225   250  25                                          CONTROL     0.05   0   240   275  35   42.5                                                          245   295  50                                                      0.1        225   285  60   47.5                                                          235   270  35                                          Ex. No.                                                                              3 IV 0.05   30  230   240  10   7.5  82                                11                     220   225   5                                                      0.1        225   245  20   17.5 63                                                       225   240  15                                                      0.05   60  210   230  20   17.5 59                                                       215   230  15                                                      0.1        200   230  30   27.5 42                                                       225   250  25                                                      0.05   90  200   215  15   15   65                                                       210   225  15                                                      0.1        205   235  30   30   37                                                       210   240  30                                                      0.05  120  205   225  20   17.5 59                                                       210   225  15                                                      0.1        200   230  30   27.5 42                                                       210   235  25                                                      0.05  180  210   230  20   17.5 59                                                       210   225  15                                                      0.1        215   240  25   30   37                                                       215   250  35                                                      0.05  240  210   235  25   20   53                                                       205   220  15                                                      0.1        225   245  20   25   47                                                       210   240  30                                                      0.05  300  215   240  25   25   41                                                       205   230  25                                                      0.1        225   245  20   27.5 42                                                       210   245  35                                          __________________________________________________________________________     SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weights(s): 415, 415 grams    

When the compounds are employed for the above utility, they may becombined with one or more pharmaceutically acceptable carriers, forexample, solvents, diluents and the like, and may be administered orallyin such forms as tablets, capsules, dispersible powders, granules, orsuspensions containing, for example, from about 0.05 to 5% of suspendingagent, syrups containing, for example, from about 10 to 50% of sugar,and elixirs containing, for example, from about 20 to 50% ethanol, andthe like, or parenterally in the form of sterile injectable solutions orsuspension containing from about 0.05 to 5% suspending agent in anisotonic medium. Such pharmaceutical preparations may contain, forexample, from about 0.05 up to about 90% of the active ingredient incombination with the carrier, more usually between about 5% and 60% byweight.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration and theseverity of the condition being treated. However, in general,satisfactory results are obtained when the compounds of the inventionare administered at a daily dosage of from about 0.5 to about 500 mg/kgof animal body weight, preferably given in divided doses two to fourtimes a day, or in sustained release form. For most large mammals thetotal daily dosage is from about 1 to 100 mg, preferably from about 2 to80 mg. Dosage forms suitable for internal use comprise from about 0.5 to500 mg of the active compound in intimate admixture with a solid orliquid pharmaceutically acceptable carrier. This dosage regimen may beadjusted to provide the optimal therapeutic response. for example,several divided doses may be administered daily or the dose may beproportionally reduced as indicated by the exigencies of the therapeuticsituation.

These active compounds may be administered orally as well as byintravenous, intramuscular, or subcutaneous routes. Solid carriersinclude starch, lactose, dicalcium phosphate, microcrystallinecellulose, sucrose and kaolin, while liquid carriers include sterilewater, polyethylene glycols, non-ionic surfactants and edible oils suchas corn, peanut and sesame oils, as are appropriate to the nature of theactive ingredient and the particular form of administration desired.Adjuvants customarily employed in the preparation of pharmaceuticalcompositions may be advantageously included, such as flavoring agents,coloring agents, preserving agents, and antioxidants, for example,vitamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease ofpreparation and administration are solid compositions, particularlytablets and hard-filled or liquid-filled capsules. Oral administrationof the compounds is preferred.

These active compounds may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inwater suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

What is claimed is:
 1. A quinazolinone compound having the formula:##STR10## wherein R is ##STR11## X is a straight or branched alkyl of 3to 5 carbon atoms; R⁶ is ##STR12## R²⁰ is H, straight chain lower alkylof 1 to 4 carbon atoms, phenyl, substituted phenyl (substitutionselected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl,nitro, 0-alkyl of 1 to 3 carbon atoms), benzyl, substituted benzyl(substitution selected from mono-lower alkyl of 1 to 3 carbon atoms,trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms);R²¹ is H,straight chain lower alkyl of 1 to 4 carbon atoms, phenyl, substitutedphenyl (substitution selected from mono-lower alkyl of 1 to 3 carbonatoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms), benzyl,substituted benzyl (substitution selected from mono-lower alkyl of 1 to3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms);R²² is H, straight chain lower alkyl of 1 to 4 carbon atoms, phenyl,substituted phenyl (substitution selected from mono-lower alkyl of 1 to3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms),benzyl, substituted benzyl (substitution selected from mono-lower alkylof 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbonatoms); R²³ is H, straight chain lower alkyl of 1 to 4 carbon atoms,phenyl, substituted phenyl (substitution selected from mono-lower alkylof 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbonatoms), benzyl, substituted benzyl (substitution selected frommono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkylof 1 to 3 carbon atoms); n is 1 or 2;or pharmaceutically acceptablesalts of these compounds.
 2. The compound according to claim 1 whereinsaid salts are selected from potassium, sodium, calcium, magnesium orammonium.
 3. The compound according to claim 1 wherein X is a straightchain alkyl of 3 to 4 carbon atoms;R⁶ is ##STR13##
 4. A quinazolinonecompound having the formula: ##STR14## wherein: X is straight orbranched alkyl of 3 to 5 carbon atoms;R⁶ is ##STR15## R²⁰ is H, straightchain lower alkyl of 1 to 4 carbon atoms, phenyl, substituted phenyl(substitution selected from mono-lower alkyl of 1 to 3 carbon atoms,trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms), benzyl,substituted benzyl (substitution selected from mono-lower alkyl of 1 to3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms);R²¹ is H, straight chain lower alkyl of 1 to 4 carbon atoms, phenyl,substituted phenyl (substitution selected from mono-lower alkyl of 1 to3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms),benzyl, substituted benzyl (substitution selected from mono-lower alkylof 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbonatoms); R²² is H, straight chain lower alkyl of 1 to 4 carbon atoms,phenyl, substituted phenyl (substitution selected from mono-lower alkylof 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbonatoms), benzyl, substituted benzyl (substitution selected frommono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkylof 1 to 3 carbon atoms); R²³ is H, straight chain lower alkyl of 1 to 4carbon atoms, phenyl, substituted phenyl (substitution selected frommono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkylof 1 to 3 carbon atoms), benzyl, substituted benzyl (substitutionselected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl,nitro, O-alkyl of 1 to 3 carbon atoms); n is 1 or
 2. 5. The compoundaccording to claim 4 wherein X is a straight chain alkyl of 3 or 4carbon atoms;R⁶ is ##STR16##
 6. A quinazolinone compound having theformula: ##STR17## wherein: X is straight or branched alkyl of 3 to 5carbon atoms;R⁶ is ##STR18## R²⁰ is H, straight chain lower alkyl of 1to 4 carbon atoms, phenyl, substituted phenyl (substitution selectedfrom mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro,O-alkyl of 1 to 3 carbon atoms), benzyl, substituted benzyl(substitution selected from mono-lower alkyl of 1 to 3 carbon atoms,trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms); R²¹ is H,straight chain lower alkyl of 1 to 4 carbon atoms, phenyl, substitutedphenyl (substitution selected from mono-lower alkyl of 1 to 3 carbonatoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms), benzyl,substituted benzyl (substitution selected from mono-lower alkyl of 1 to3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms);R²² is H, straight chain lower alkyl of 1 to 4 carbon atoms, phenyl,substituted phenyl (substitution selected from mono-lower alkyl of 1 to3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms),benzyl, substituted benzyl (substitution selected from mono-lower alkylof 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbonatoms); R²³ is H, straight chain lower alkyl of 1 to 4 carbon atoms,phenyl, substituted phenyl (substitution selected from mono-lower alkylof 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbonatoms), benzyl, substituted benzyl (substitution selected frommono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkylof 1 to 3 carbon atoms); n is 1 or
 2. 7. The compound according to claim6 wherein X is a straight chain alkyl of 3 or 4 carbon atoms;R⁶ is##STR19##
 8. A quinazolinone compound having the formula: ##STR20##wherein: X is a straight or branched alkyl of 3 to 5 carbon atoms;R²⁰ isH, straight chain lower alkyl of 1 to 4 carbon atoms, phenyl,substituted phenyl (substitution selected from mono-lower alkyl of 1 to3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms),benzyl, substituted benzyl (substitution selected from mono-lower alkylof 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbonatoms); R²¹ is H, straight chain lower alkyl of 1 to 4 carbon atoms,phenyl, substituted phenyl (substitution selected from mono-lower alkylof 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbonatoms), benzyl, substituted benzyl (substitution selected frommono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkylof 1 to 3 carbon atoms); R²² is H, straight chain lower alkyl of 1 to 4carbon atoms, phenyl, substituted phenyl (substitution selected frommono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkylof 1 to 3 carbon atoms), benzyl, substituted benzyl (substitutionselected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl,nitro, O-alkyl of 1 to 3 carbon atoms); R²³ is H, straight chain loweralkyl of 1 to 4 carbon atoms, phenyl, substituted phenyl (substitutionselected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl,nitro, O-alkyl of 1 to 3 carbon atoms), benzyl, substituted benzyl(substitution selected from mono-lower alkyl of 1 to 3 carbon atoms,trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms); n is 1 or
 2. 9.A quinazolinone compound having the formula: ##STR21## wherein: X is astraight or branched alkyl of 3 to 5 carbon atoms;R²⁰ is H, straightchain lower alkyl of 1 to 4 carbon atoms, phenyl, substituted phenyl(substitution selected from mono-lower alkyl of 1 to 3 carbon atoms,trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms), benzyl,substituted benzyl (substitution selected from mono-lower alkyl of 1 to3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms);R²¹ is H, straight chain lower alkyl of 1 to 4 carbon atoms, phenyl,substituted phenyl (substitution selected from mono-lower alkyl of 1 to3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms),benzyl, substituted benzyl (substitution selected from mono-lower alkylof 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbonatoms); R²² is H, straight chain lower alkyl of 1 to 4 carbon atoms,phenyl, substituted phenyl (substitution selected from mono-lower alkylof 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbonatoms), benzyl, substituted benzyl (substitution selected frommono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkylof 1 to 3 carbon atoms); R²³ is H, straight chain lower alkyl of 1 to 4carbon atoms, phenyl, substituted phenyl (substitution selected frommono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkylof 1 to 3 carbon atoms), benzyl, substituted benzyl (substitutionselected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl,nitro, O-alkyl of 1 to 3 carbon atoms); n is 1 or
 2. 10. A quinazolinonecompound having the formula: ##STR22## wherein: X is a straight orbranched alkyl of 3 to 5 carbon atoms;R²⁰ is H, straight chain loweralkyl of 1 to 4 carbon atoms, phenyl, substituted phenyl (substitutionselected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl,nitro, O-alkyl of 1 to 3 carbon atoms), benzyl, substituted benzyl(substitution selected from mono-lower alkyl of 1 to 3 carbon atoms,trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms); R²¹ is H,straight chain lower alkyl of 1 to 4 carbon atoms, phenyl, substitutedphenyl (substitution selected from mono-lower alkyl of 1 to 3 carbonatoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms), benzyl,substituted benzyl (substitution selected from mono-lower alkyl of 1 to3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms);R²² is H, straight chain lower alkyl of 1 to 4 carbon atoms, phenyl,substituted phenyl (substitution selected from mono-lower alkyl of 1 to3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms),benzyl, substituted benzyl (substitution selected from mono-lower alkylof 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbonatoms); R²³ is H, straight chain lower alkyl of 1 to 4 carbon atoms,phenyl, substituted phenyl (substitution selected from mono-lower alkylof 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbonatoms), benzyl, substituted benzyl (substitution selected frommono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkylof 1 to 3 carbon atoms); n is 1 or
 2. 11. A quinazolinone compoundhaving the formula: ##STR23## wherein: X is a straight or branched alkylof 3 to 5 carbon atoms;R⁶ is ##STR24## R²⁰ is H, straight chain loweralkyl of 1 to 4 carbon atoms, phenyl, substituted phenyl (substitutionselected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl,nitro, O-alkyl of 1 to 3 carbon atoms), benzyl, substituted benzyl(substitution selected from mono-lower alkyl of 1 to 3 carbon atoms,trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms); R²¹ is H,straight chain lower alkyl of 1 to 4 carbon atoms, phenyl, substitutedphenyl (substitution selected from mono-lower alkyl of 1 to 3 carbonatoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms), benzyl,substituted benzyl (substitution selected from mono-lower alkyl of 1 to3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms);R²² is H, straight chain lower alkyl of 1 to 4 carbon atoms, phenyl,substituted phenyl (substitution selected from mono-lower alkyl of 1 to3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms),benzyl, substituted benzyl (substitution selected from mono-lower alkylof 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbonatoms); R²³ is H, straight chain lower alkyl of 1 to 4 carbon atoms,phenyl, substituted phenyl (substitution selected from mono-lower alkylof 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbonatoms), benzyl, substituted benzyl (substitution selected frommono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkylof 1 to 3 carbon atoms); n is 1 or
 2. 12. The compound according toclaim 11 wherein X is a straight chain alkyl of 3 or 4 carbon atoms;R⁶is ##STR25##
 13. The compound according to claim 12-butyl-6-(3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]-pyrazol-2-yl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone.14. The compound according to claim 12-butyl-6-(3,3a,4,5,6,7-hexahydropyrazolo[1,5-a]-pyridin-2-yl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl-4(3H)-quinazolinone.15. The compound according to claim 64'-[[2-butyl-6-(3,3a,4,5,6,7-hexahydro-pyrazolo-[1,5-a]pyridin-2-yl)-4-oxo-3(4H)-quinazolinyl]-methyl][1,1'-biphenyl]-2-carbonitrile.16. The compound according to claim 64'-[2-butyl-4-oxo-6-(3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3(4H)-quinazolinyl][1,1-biphenyl]-2-carbonitrile.17. The compound according to claim 94'-[[2-butyl-4-oxo-6-[2-(4-pentenyl)-2H-tetrazol-5-yl]-3(4H)-quinazolinyl]methyl]-[1,1'-biphenyl]-2-carbonitrile.18. The compound according to claim 102butyl-6-[2-(4-pentenyl)-2H)-tetrazol-5-yl]-4(1H)-quinazolinone.
 19. Apharmaceutical composition useful for treating angiotensin inducedhypertension or congestive heart failure in a mammal comprising asuitable pharmaceutical carrier and an effective amount of a compound ofclaim
 1. 20. A method of treating angiotensin induced hypertension in amammal comprising administering a compound of claim 1 to said mammal anamount effective to lower angiotensin induced hypertension.
 21. A methodof treating congestive heart failure in a mammal comprisingadministering a compound of claim 1 to said mammal in an amounteffective to treat congestive heart failure.
 22. A method antagonizingthe effects of angiotensin II in a mammal comprising administering acompound of claim 1 to said mammal in an amount effective to treat theeffects of angiotensin II.